Tiotropium bromide (1), first disclosed in EP0418716, is a highly effective anticholinergic agent with specificity for muscarinic receptors and it is presently approved for the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Tiotropium bromide is used in low (microgram) therapeutic doses and it is therefore particularly necessary to develop an industrial process for the commercial preparation of tiotropium bromide which ensures that the product is prepared not only in a high, economical yield but also with exceptional chemical and polymorphic purity.
The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound, which is the active ingredient, has handling difficulties during the manufacturing process and may impart undesirable properties to the final drug or dosage form. In addition it can be difficult to control the polymorphic form of the active pharmaceutical ingredient throughout the manufacturing process.
For pharmaceuticals in which the active ingredient can exist in more than one polymorphic or crystalline form, it is particularly important to ensure that the manufacturing process for the active ingredient affords a single, pure polymorph with a consistent level of polymorphic purity. If the manufacturing process leads to a polymorph with varying degrees of polymorphic purity and/or or where the process does not control polymorphic interconversion, serious problems in dissolution and/or bioavailability can result in the finished pharmaceutical composition comprising the active ingredient.
If crystalline forms are made with polymorphic impurities, this causes instability and it can accelerate significant interconversion to another polymorphic form. Therefore it is crucial to produce crystalline forms with very high polymorphic purity to avoid this interconversion.
A process for the preparation of tiotropium bromide was first reported in EP0418716. Tiotropium bromide monohydrate is disclosed in WO2002/30928 along with a method of its preparation by heating anhydrous tiotropium bromide in water in the presence of activated charcoal. In addition, there have been several subsequent disclosures of methods to prepare anhydrous tiotropium bromide from tiotropium bromide monohydrate or solvate.
A method of preparing anhydrous tiotropium bromide by heating tiotropium bromide monohydrate at 80-100° C. under vacuum is disclosed in U.S. Pat. No. 6,608,055. However, this method is not suitable for commercial manufacture as directly heating a solid at high temperature can lead to localized heating and inconsistent results.
Another method disclosed in U.S. Pat. No. 6,608,055 involves the conversion of tiotropium bromide monohydrate to anhydrous tiotropium bromide by storing over silica gel for 24 hours. However, this method is not amenable to commercial manufacturing.
An alternative method of preparing anhydrous tiotropium bromide, disclosed in WO2007/075858, involves heating tiotropium bromide methanolate or hemi-n-butanolate or hemi-acetate in an oven at 160° C. This requires very high temperatures and specific solvates as starting material.
Another method, disclosed in US2005/0143410, involves a process for converting tiotropium bromide monohydrate to anhydrous tiotropium bromide by boiling in water and adding ammonium fluoride. Alternatively, a crystallization method from methanol with seeding was reported.
A further method, disclosed in US2007/0092453, involves converting tiotropium bromide monohydrate to anhydrous tiotropium bromide by heating at 50° C. in a 1:1 N,N-dimethylacetamide/water mixture. Also reported are 14 different solvates of tiotropium bromide. However, this method in US2007/0092453 involves evaporation of high volumes of high boiling solvents at room temperature under a vacuum of 1 Kpa until crystals appear in the solution. The method is not particularly reproducible and as both N,N-dimethylacetamide and water are high boiling solvents (164° C. and 100° C. respectively), the removal of these solvents at room temperature requires high vacuum. Therefore removal of such volumes of N,N-dimethylacetamide and water at room temperature is practically very difficult for production on a commercial scale. In addition, the process is limited to tiotropium bromide monohydrate as starting material.
From the above prior art details, it can be observed that there is no direct method reported in the literature for preparing anhydrous tiotropium bromide. All the above processes reported for preparing anhydrous tiotropium bromide involve the preparation of either tiotropium bromide monohydrate or tiotropium bromide solvates as starting material to prepare anhydrous tiotropium bromide. This increases the number of steps and reduces the overall yield.
Hence it would be advantageous to have a direct method for preparing anhydrous tiotropium bromide which does not involve the preparation of either tiotropium bromide monohydrate or a tiotropium bromide solvate as starting material.
In addition, the processes described in the prior art typically require elevated temperatures and therefore can lead to impure products, since it has been observed that tiotropium bromide decomposes at higher temperatures generating scopine di-(2-thienyl)glycolate as an impurity. Consequently, there is a requirement for an additional purification step to afford pure anhydrous tiotropium bromide as it typically contains 0.1-0.5% of impurity scopine di-(2-thienyl)glycolate. In addition, the anhydrous tiotropium bromide formed in the prior art processes is not polymorphically pure.
In view of the importance acquired by tiotropium bromide for the treatment of respiratory disorders, there is a great need for developing an alternative, relatively simple, economical and commercially feasible process for the synthesis of tiotropium bromide crystalline forms with commercially acceptable yield, chemical purity and high polymorphic purity and polymorphic stability.